Advances in antiviral treatment of HIV infection, along with developments in the prophylaxis and therapy of opportunistic infections, have greatly improved the long-term health of HIV-infected individuals. However, along with improved antiretroviral therapy a new syndrome has developed, which is identified herein as HIV-associated dysmorphia/dysmetabolic syndrome, or HIV-associated adipose redistribution syndrome (HARS), or hereafter abbreviated HADDS.
HADDS involves pathological accumulation of adipose tissue in specific regional depots. The pathologic adipose tissue accumulation of HADDS may also be associated with abnormal adipose tissue depletion elsewhere (lipodystrophy or lipoatrophy), with or without associated metabolic abnormalities, premature atherosclerotic lesions, depletion of lean body mass, and/or other abnormal physiology.
This recently discovered clinical disorder, which has been referred to by a number of terms, including HIV lipodystrophy syndrome and other terminology, has important public health consequences, as described further below.
HADDS patients typically present with abnormal accumulation of adipose tissue in the abdomen, specifically in the visceral adipose tissue compartment (Miller et al, 1998, Kotler et al, 1999; Engelson et al, 1999). HADDS patients may also present with abnormal adipose tissue accumulation in the dorsocervical area (“buffalo hump”), the submandibular area (“horse collar”), the pectoral, mammary, and/or supraclavicular areas, and/or with subcutaneous lipomas (encapsulated benign fatty tumors, single or multiple).
Abnormal, involuntary, pathological, and often dysmorphic accumulation of adipose tissue is sufficient to diagnose a HIV-infected patient with HADDS. However, in addition to developing abnormal adipose accumulation, some HADDS patients develop abnormally depleted subcutaneous adipose tissue, termed “peripheral lipodystrophy” (or lipoatrophy) at other specific sites. This adipose depletion is typically observed in the face (buccal, parotid, and periauricular fat pads), and in the subcutaneous adipose tissue surrounding the limbs, trunk, and/or gluteal regions. Also, some HADDS patients may present with metabolic abnormalities (Carr et al, 1998a, 1998b, 1999a, 1999b; Lipodystrophy Rapid Report, 1999).
The metabolic abnormalities associated with HADDS and lipodystrophy syndrome typically involve disordered lipid and glucose metabolism. Clinical manifestations may include fasting hypertriglyceridemia, hyperlipidemia, and abnormalities of the insulin/glucose axis (elevated fasting insulin, elevated C-peptide, insulin resistance or reduced insulin sensitivity), with or without overt diabetes (Carr et al, 1998a, 1998b, 1999a, 1999b; Henry et al, 1998; Grunfeld, 1999).
Abnormal adipose tissue accumulation abnormalities occur more frequently in female than male cases diagnosed with HADDS, while fat depletion, hyperglycemia, and hyperlipidemia are more commonly observed in male cases (Muurahainen, 1999). Hence the presentation of HADDS appears to vary by gender.
There are preliminary reports suggesting that patients with HADDS exhibit preclinical evidence of increased risk for coronary heart disease (CHD). Preclinical indicators of CHD include increased coronary artery calcification (CAC) as quantified by electron beam computed tomography (EBCT), and extracoronary indicators such as increased intima media thickening (IMT) in the carotid artery and impaired blood flow-mediated dilation in the brachial artery, as quantified by ultrasonography, which signify endothelial dysfunction that may lead to atherosclerosis and CHD. In eight patients with HADDS who developed increased abnormal girth with abnormally accumulated visceral adipose tissue after initiation of HIV protease inhibitor (PI) therapy who underwent EBCT, Kosmiski et al (1999) reported a mean CAC score consistent with minimal identifiable plaque burden. There are also preliminary reports indicating that HIV patients receiving PIs display abnormal carotid IMT (Maggi et al, 1999) and impaired brachial flow-mediated dilation (Stein, 1999), signifying endothelial dysfunction. However, it is unclear which, if any, of the patients in the two aforementioned preliminary reports were HADDS patients, and what percentage of HADDS patients have preclinical indicators of abnormal endothelial function.
There have also been case reports of premature coronary artery disease in HIV patients under age forty who have been receiving combination antiretroviral therapy that include a protease inhibitor (Henry et al, 1998). However, it may take years before well-designed, prospective, observational cohort studies precisely quantify the risk of premature coronary artery disease in patients with HADDS.
Some patients with HADDS also exhibit involuntary weight loss with depletion of lean body mass (AIDS wasting or cachexia), and possibly depletion of lean body mass without overt weight loss (occult wasting) (Muurahainen, unpublished observations, data on file, Serono Laboratories, Norwell, Mass.).
Other abnormal physiology that may be observed in patients with HADDS or lipodystrophy syndrome include gout and pancreatitis (presumably resulting from severe hypertriglyceridemia), hepatic steatosis (possibly reflecting chronic lactic acidosis), hypogonadism, and possibly other hormonal abnormalities (Henry et al, 1998; Brinkman, 1999; Lipodystrophy Rapid Report, 1999).
HADDS and lipodystrophy syndrome may or may not be associated with other abnormalities, such as cutaneous abnormalities (such as thinning hair, hair loss, hair brittleness, dry skin, abnormal nails, ingrown toenails), disorders of the coagulation syndrome that result in increased bleeding in hemophiliacs, osteoporosis or avascular necrosis of the hips, peripheral neuropathy, nausea, fatigue, weight loss, chronic diarrhea, fever, mennorhagia and menstrual abnormalities, impaired sexual dysfunction (decreased libido, erectile dysfunction), and abnormalities of the genitalia resembling Peyronie's Disease (Carr et al, 1998a, 1998b, 1999a, 1999b; Lipodystrophy Rapid Report, 1999).
In sum, HADDS is a recently discovered multisystemic, gender dimorphic disorder associated with HIV infection that includes (1) regional changes in adipose distribution, frequently dysmorphic, that result from abnormal regional accumulation of adipose tissue, with or without lipodystrophy, (2) occasionally observed in conjunction with abnormalities of lipid and glucose metabolism, and (3) possibly associated with other physiologic abnormalities, including premature atherosclerotic lesions, depletion of lean body mass, and other abnormalities.
Since HADDS and HIV-associated lipodystrophy syndrome have only recently been described, standardized nomenclature or consensus definition(s) for these syndromes are lacking. Kotler and Schambelan (1999) predict that we may eventually see an official case definition that has major and minor criteria, similar to what is already in place for rheumatic disorders such as systemic lupus erythematosis (Kotler and Schambelan, 1999).
In recent years, a plethora of terms and nomenclature have been used by scientists, clinicians, and patient advocates to describe the syndrome and its manifestations. Any of the manifestations may be observed in men, women, and children with HIV infection who develop the syndrome. The terms describing it may be found in the peer-reviewed scientific literature, posted in discussions and reviews on the internet. The terms provided below are non-inclusive. New terms are continually added.
Terms that have been used to describe the syndrome or subsets of it include: HIV-associated dysmorphia/dysmetabolic syndrome (HADDS); HIV-associated adipose redistribution syndrome (HARS); lipodystrophy syndrome and HIV-associated lipodystrophy syndrome (HALS); HIV-related peripheral lipodystrophy (HIPL); HIV-associated fat redistribution syndrome (HIVFRES) or fat redistribution syndrome (FRS); fat maldistribution syndrome (FMS), HIV-associated dysmorphia/metabolic Syndrome (HADMS), abnormal body fat (ABF) accumulation, and protease inhibitor-associated lipodystrophy (PI-AL).
Terms used to describe abnormal accumulation of abdominal adipose tissue in patients with the syndrome include: HIV-associated “Crix belly” and “protease paunch” (although the truncal adiposity may not be directly related to Crixivan or other protease inhibitors); “pouch belly”; truncal adiposity, truncal obesity, central obesity, abdominal adiposity, increased waist to hip ratio (WHR), increased waist-to-thigh circumference ratio (by anthropometry), increased truncal to limb fat ratio (by DXA scan), increased abdominal visceral adipose tissue (VAT) with decreased subcutaneous adipose tissue (SAT) and increased VAT/SAT ratio by CT or MRI scan, and “Pseudo-Cushing's syndrome”.
Terms used to describe other types of fat accumulation in patients with HADDS include HIV-related buffalo hump, abnormal accumulation of dorsocervical fat, “dorsocervical lipodystrophy” (a misnomer because it implies depletion of the dorsocervical fat pad), increased neck fat, facial fat accumulation, double chin, moon face, submandibular fat accumulation (“horse collar”), supraclavicular fat pad accumulation, multiple symmetric lipomatosis, “lumps and bumps”, Madelung's syndrome, HIV-related breast enlargement, mammary fat hyperplasia and gynecomastia. (Note that it is unclear if there is true gynecomastia, or whether there is hypertrophy of subcutaneous chest fat other than mammary tissue), “chest fat accumulation”, and peripheral adiposity.
Terms used to describe abnormal depletion of adipose tissue found in some patients with HADDS and lipodystrophy syndrome include: pseudocachexia, peripheral lipodystrophy, pure lipoatrophy, “Lipo”, facial wasting, facial wrinkling, sunken cheeks, sunken eyes, temple hollowness, prominent zygomatic arch, “cadaveric facies”, buccal, parotid, and periauricular fat pad wasting, limb wasting, skinny, stick arms and stick legs with symmetrical, prominent non-varicose veins, muscularity and bones, butt wasting, saggy buttocks with loose skin folds, loss of buttock fat contour, and hollowing of the buttocks.
For the purpose of the invention described herein, a distinction is made between HADDS and HIV lipodystrophy syndrome. Several types of HIV-related lipodystrophy syndrome(s) have been described: patients presenting only with adipose tissue accumulation, those presenting adipose accumulation and depletion (“mixed syndrome”), and those presenting only with adipose tissue depletion (“pure lipoatrophy”) (Rosenbaum, 1999; Saint-Marc, 1999; Thiebaut et al, 1999; Viard, 1999).
For the purpose of the invention described herein, HADDS patients are considered to be a subset of patients with HIV-related lipodystrophy syndrome who exhibit abnormal adipose tissue accumulation. HADDS patients are lipodystrophy patients who exhibit either adipose accumulation alone or adipose accumulation associated with adipose depletion elsewhere (“mixed syndrome”). The rationale for focusing on HADDS patients as a clinically important subset of patients with lipodystrophy syndrome, is that patients with abnormally accumulated adipose tissue are the ones for whom the invention, a lipolytic (adipose-depleting) agent, will be recommended as a treatment, in contrast to patients with lipodystrophy syndrome who exhibit only adipose tissue depletion, or pure lipoatrophy.
For purposes of the invention described herein, it makes sense from a scientific perspective to focus on the treatment of pathologically accumulated adipose tissue with associated metabolic and physiologic abnormalities, rather than to focus on treatments for depleted adipose tissue. As discussed further below, excess accumulation of visceral adipose tissue has been associated with adverse clinical outcomes. The long term clinical consequences of adipose tissue depletion alone (pure lipoatrophy per se), if any, are presently unknown.
Since 1997, the unusual and unexpected morphologic features that comprise HADDS and HIV-related lipodystrophy syndrome have been increasingly observed and reported. Manifestations of the syndrome were first observed in conjunction with use of highly active combination antiretroviral therapies that included an HIV protease-inhibiting agent (Carr et al, 1998a, 1998b, 1999a, 1999b; Lo et al, 1998), but the manifestations have also been observed in HIV patients who have never received protease inhibitors (Lo et al, 1998; Kotler, 1998; Carr et al, 1999a, 1999b; Mercie et al, 1999; Gervasconi, 1999; Hadigan et al, 1999; Brinkman, 1999).
Abnormal adipose tissue accumulation, the primary pathologic lesion of HADDS may develop rapidly (within weeks to months after initiating a new antiretroviral regimen) or may develop gradually over periods of one to several years. The etiology of the syndrome is unknown. It is unclear whether the HADDS and lipodystrophy syndromes are drug-related, and if they are drug-related, what antiretroviral agents or classes of agents are causal. Both HIV-1 protease inhibitors and HIV-1 reverse transcriptase inhibitors have been proposed as etiologic agents (Carr et al, 1998a, 1998b, 1999a, 1999b; Saint-Marc, 1999; Brinkman, 1999).
Although manifestations of HADDS and lipodystrophy syndrome are more prevalent in HIV/AIDS patients who have received combination antiretroviral therapies (especially highly active antiretroviral therapy with protease inhibitors), in some cases the syndrome or some of its manifestations have been observed in patients who have never received antiretrovirals (Lo et al, 1998; Carr et al, 1998a, 1998b, 1999a, 1999b; Mercie et al, 1999).
Manifestations of the syndrome sometimes partially abate when antiretroviral medications are discontinued or changed, but the manifestations often do not abate completely or resolve relatively for many months or up until a year after the switch in therapy (Saint-Marc, 1999; Rosenbaum, 1999; Ruiz, 1999; Moyle; 1999, Gatell; 1999). This raises a concern that the syndrome might occur in conjunction with immune reconstitution or autoimmune phenomena associated with chronic suppression of HIV-1 (Kotler, 1998).
As mentioned previously, for a number of reasons the dysmorphic bodily changes and metabolic manifestations of HADDS are of important public health significance. Abnormal adipose accumulation becomes clinically significant when it results in physical discomfort or disability due to a variety of symptoms, including the following types of symptoms: headaches and inability to fully extend the neck due to buffalo hump; abdominal cramping, indigestion, constipation, shortness of breath and respiratory insufficiency, or ventral hernias due to rapid accumulation of excess visceral adipose tissue. Abnormal accumulation of visceral adipose tissue is also a significant independent risk factor for cardiovascular disease.
The physical manifestations of HADDS are also of public health significance because these manifestations are perceived by many patients to be disturbing, disfiguring, appalling, stigmatizing, and/or threatening loss of privacy. Some patients with the syndrome develop body image disturbance, depression, and agoraphobia (Cheng, 1999; Forum for HIV Collaborative Research, 1999). The unusual and increasingly well-recognized physical characteristics of HADDS such as buffalo hump, truncal obesity, breast enlargement, horse collar, supraclavicular fat pads, facial and limb wasting, and lipomas have the potential to become socially stigmatizing because these recognizable features instantly reveal that a patient probably has HIV/AIDS (“a forced form of HIV identification”, according to Cheng (1999), as cited in Lipodystrophy Rapid Report (1999)).
Concerns about health, appearance, potential stigmatization and loss of privacy in the workplace and elsewhere, may lead some patients with HADDS to discontinue otherwise effective antiretroviral therapy (Struble and Piscitelli, 1999). These concerns may also lead other HIV patients to refuse to initiate medically necessary antiretroviral therapies for fear of developing the syndrome and the increased medical risks associated with it (Cheng, 1999). This could eventually lead to increased HIV infectivity, more opportunistic complications, and increased medical costs.
The increased cardiovascular risk factors associated with HADDS are also of important public health significance. These risk factors include abnormally accumulation of visceral adipose tissue, hyperlipidemia, hyperinsulinemia, and premature atherosclerotic changes associated in HADDS, may result in increased risk for cardiovascular disease and stroke (Henry et al, 1998).
Other metabolic manifestations associated with HADDS syndrome also have the potential to become medically significant problems warranting therapeutic intervention. These metabolic manifestations include sudden, severe hyperglycemia, new-onset diabetes mellitus, pancreatitis and gout due to pronounced hypertriglyceridemia, and difficult-to-manage hyperlipidemia that may include elevated total cholesterol, elevated low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol, and other lipoprotein abnormalities associated with increased cardiovascular risk (Henry et al, 1998).
With respect the invention described herein, it is worth noting that antiretroviral agents (especially HIV protease inhibitors) undergo substantial hepatic metabolism. It is difficult to pharmacologically manage hyperlipidemia and hyperinsulinemia in HIV patients receiving combination antiretroviral therapy because the antiretroviral agents typically interact with anti-hyperlipidemics (statins, fibrates) and anti-hyperglycemic agents (thiazides and glitazones), which also undergo significant hepatic metabolism (Henry et al, 1998). A therapy such as the invention described herein, using an agent which is not primarily metabolized by the liver, and which has the potential to reduce hyperlipidemia and improves insulin sensitivity while depleting abnormally accumulated visceral adipose tissue, may be of special value in the treatment of HADDS.
Moreover, other physiologic abnormalities that have been suggested to be evaluated as part of research to develop a case definition of lipodystrophy syndrome, which may ultimately be associated with HADDS, may warrant therapeutic intervention (Lipodystrophy Rapid Report, 1999). These abnormalities include hypertension, hypogonadism, impaired sexual function (decreased, erectile dysfunction), menstrual irregularities, hair loss, dry skin, and ingrown toenails that can become infected, peripheral neuropathy, liver steatosis, osteoporosis with bone fractures and avascular necrosis of the hips, and derangement of the complement system with coagulation disorders, leading to increased bleeding in hemophiliacs.
Regarding excess adipose tissue accumulation in HADDS, the key pathological abnormality associated with this syndrome, it is worth noting that abnormal adipose accumulation is typically more pronounced regionally than in the body as a whole (Carr et al, 1998a, 1998b; Engelson et al, 1999; Kotler et al, 1999). Since regional adipose deposition in patients with HADDS may occur in conjunction with depletion of subcutaneous adipose tissue elsewhere, and/or depletion lean body mass, whole body fat accumulation and weight may not change significantly as a patient develops HADDS. It should also be noted that in order to diagnose HADDS, techniques that enable one to assess regional accumulation of adipose tissue are needed. Clinical assessment may include patient and provider history of changes in body habitus, anthropometry, serial photography, DXA, CT, and/or MRI scanning).
The most common presentation of regional fat accumulation in patients with HADDS is truncal obesity or visceral adiposity. Carr et al (1998) documented increased truncal fat in a majority (64%) of their protease inhibitor-treated subjects using the technique of dual-energy X-ray absorptiometry (DXA). Muurahainen at al (1999) found that 70 to 90% their cases reported increased abdominal girth as documented by patient self assessment questionnaire that was corroborated by physician report.
It has been demonstrated in that the truncal adipose tissue observed by DXA and increased abdominal girth reported by patients with HADDS primarily reflects abnormal accumulation of visceral adipose tissue (Miller et al, 1998; Kotler et al, 1999; Engelson et al, 1999). Miller et al (1998) reported that some patients experienced an increase in abdominal girth with symptoms of abdominal fullness, distension, or bloating after adding indinavir, a protease inhibitor, to combination drug regimens for HIV-1 infection. In several patients with these symptoms, abdominal computed-tomography (CT) scans revealed an excess amount of intra-abdominal fat and a relative paucity of subcutaneous fat.
Using whole body magnetic imaging resonance (MRI) technology to quantify abdominal fat, Kotler and colleagues reported that the increased girth in HIV patients with truncal obesity represented pathological accumulation of visceral adipose tissue in conjunction with depletion of subcutaneous adipose tissue (Kotler et al, 1998; Engelson et al, 1999). Not all of these patient received HIV protease inhibitors. The visceral adipose tissue depot included omental adipose tissue surrounding the intestines along with pelvic and perinephric adipose tissue (Engelson et al, 1999). The visceral adipose tissue (VAT) accumulation observed in patients with HADDS is typically two to seven times standard deviations above the mean for VAT in gender and age-matched healthy controls (Kotler, personal communication, 1999, manuscript in preparation).
Other types of abnormal adipose tissue accumulation in patients with HADDS include buffalo hump (dorsocervical fat pad), enlargement of the submandibular or supraclavicular fat pads with apparent bulging, lipomas (single or multiple) and increased accumulation of adipose tissue in the chest or breast area, observed more frequently in women more than in men (Dong K et al, 1998; Falutz, 1999; Gervasconi et al, 1999; Muurahainen, 1999).
Regarding buffalo hump, Lo et al (1998) reported the results of studies done in eight HIV-1-positive patients referred for investigation abnormal accumulation of adipose tissue in the dorsocervical area. Only 50% of these patients were receiving triple antiretroviral regimens that included a protease inhibitor. No other signs of Cushing's Syndrome were present in the patients. The fact that 50% of the patients with buffalo hump had no history of protease-inhibitor use indicates that development of non-Cushingoid buffalo hump is not unique to patients receiving protease-inhibitor therapy. The mechanism of further increase in triglyceride values in patients with buffalo hump is not certain, although a possible relation between increased triglyceride concentration and atypical body-fat distribution should be considered. For example, central fat accumulation may lead to the metabolic syndrome of insulin resistance, hypertriglyceridemia and hypertension if the major component gained is visceral fat.
The subcutaneous adipose tissue depletion (lipodystrophy, or lipoatrophy) that is often observed HADDS patients includes thinning of the skin on the arms and legs, with venous prominence. There is also thinning of facial fat with increased wrinkling of the face, especially in the nasolabial folds. Sometimes hollow sunken cheeks are observed. Viraben et al (1998) reported a case series involving eight patients who developed either partial or generalized lipodystrophy after protease inhibitor therapy. While two patients developed progressive loss of subcutaneous fat from both legs, excess fat deposition in the unaffected buttocks and abdomen gave an impression of obesity. In six cases, a cachetic appearance was observed resulting from the loss of buccal, parotid and preauricular fat pads. Two patients exhibited a generalized loss of fatty tissue from the face. In 50% (four) of the patients in this case series, either diabetes or insulin resistance was also discovered.
Metabolic abnormalities do not occur in every patient with HADDS, and not every HIV patient who develops metabolic abnormalities (while receiving protease inhibitors, other antiretroviral agents, or receiving no agents at all) concurrently develops abnormal fat accumulation. Mulligan et al (1998) compared results obtained in patients before and after beginning an antiretroviral regimen that included a protease inhibitor or lamivudine. No significant changes in total or regional fat or lean body mass were found by dual-energy X-ray absorptiometry in any group over the short time period of about four months. Miller et al (1998) found no relationships among CT-diagnosed visceral fat accumulation, hypertriglyceridemia, and hypercholesterolemia. Other investigators have also reported that abnormal adipose tissue accumulation in HIV patients is not always associated with hyperlipidemia or abnormal insulin/glucose metabolism (Lo et al, 1998; Muurahainen, 1999; Kotler and Schambelan; 1999).
Regarding disturbances of glucose and insulin metabolism, the FDA reported that there were reports of insulin resistance in patients receiving protease inhibitors for treatment HIV infection, and some of these diabetic patients were found to have truncal obesity (FDA, 1997). However, those who have since reviewed diabetes associated with the use of protease inhibitors have concluded that protease inhibitor-induced hyperglycemia appears to be a rare occurrence (Dong B J et al, 1998; Keruly, 1998).
With respect to fasting hypertriglyceridemia, this abnormality was first reported and associated with HIV infection, in the absence of antiretroviral therapies and abnormal adipose tissue accumulation (Grunfeld, 1992). Patients with hypertriglyceridemia prior to starting combination antiretroviral therapy appear to have an exacerbation of the condition while on combination therapy and do not return to their previous state.
With respect to hypercholesterolemia and other metabolic abnormalities in HIV patients on combination antiretroviral therapy, serum cholesterol concentrations rise, though rarely to dangerously high levels (Carr et al, 1998a, 1998b, 1999a, 1999b; Henry et al, 1998). Some patients developed hypertension and, in others, low serum testosterone concentrations developed or pre-existing hypogonadism persisted.
From the lack of tight associations described above, it is unclear if administration of protease inhibitors produces lipodystrophy syndrome or HADDS. Carr et al (1998), who described peripheral lipodystrophy and unusual fat accumulation in HIV-infected patients receiving protease inhibitors which, together with the known side effects of protease inhibitors of hyperlipidemia and diabetes mellitus, have suggested that protease inhibitors cause metabolic perturbations leading to insulin resistance. Carr also found evidence of insulin resistance in patients with lipodystrophy syndrome, although clinically apparent diabetes mellitus was very uncommon. An amino acid sequence in the catalytic site of HIV protease was found to have a significant homology with a low density lipoprotein receptor-like protein. These results tend to implicate the protease inhibitors themselves in the development of this problem.
However, other researchers have found that the protease inhibitors per se are not always associated with the morphologic and metabolic abnormalities of lipodystrophy syndrome and HADDS (Lo et al, 1998; Kotler et al, 1998; Brinkman 1999; Carr, 1999b; Gervasconi, 1999; Hadigan et al, 1999). Morphologic and metabolic changes are not seen consistently in all protease inhibitor-treated patients, and many patients have only certain elements of the syndrome. In some cases the abnormal morphologic and/or metabolic manifestations have been observed in patients who have never received any type of antiretroviral medication (Lo et al, 1998; Carr et al, 1998a, 1998b, 1999a, 1999b; Mercie et al, 1999).
Even though HIV patients with visceral adiposity and buffalo hump have phenotypes that are reminiscent of Cushing's syndrome, it is unlikely that HADDS patients will have Cushing's syndrome. In a case series of HIV patients with buffalo hump, Lo et al (1998) found that fasting serum cortisol concentrations and standard dexamethasone suppression tests were normal. In a case series of HIV patients with abnormal visceral adipose tissue accumulation (Kotler et al, 1998), and in one of the patients of with buffalo hump (Lo et al, 1998) moderate elevations in 24-hour urinary-free cortisol were observed. However, even though there may be subtle abnormalities in cortisol in patients with HADDS, so far Cushing's syndrome has been ruled out in all of them by the standard dexamethasone suppression test.
As mentioned above, the possibility of concomitant AIDS wasting and/or depletion of lean body mass a consideration in HADDS. Despite advances in treating the retrovirus infection and the complications of AIDS, some HIV-infected patients still develop overt AIDS wasting (or cachexia), which involves profound depletion of weight and lean body mass. Overt AIDS wasting, defined as an involuntary weight loss exceeding 10% of usual body weight, has become less prevalent since the widespread use of highly active antiretroviral therapy, and probably occurs in fewer than 10% of patients receiving highly active antiretroviral therapy (Mocroft, 1999). Similarly, in one large case series, fewer than 10% of HADDS patients exhibited overt AIDS wasting (Muurahainen et al, unpublished observations).
However, HIV patients may also present with “occult wasting”, defined as a significant depletion of lean body mass without significant weight loss (Muurahainen, 1994). The prevalence of occult wasting in patients with HADDS is currently under investigation. Since occult wasting may occur in patients receiving combination antiretroviral therapy (Muurahainen, 1994; Gibert, 1996), it is possible that patients with HADDS will also display depletion of lean body mass without weight loss, or occult wasting.
To summarize, HADDS is newly discovered a HIV-related syndrome involving relatively rapid, pathologic accumulation of adipose tissue in specific depots that develops over a period of several months to years, frequently in association with subcutaneous peripheral lipodystrophy (facial and limb wasting), and occasionally associated with hyperlipidemia and hyperinsulinemia, in the absence of hypercortisolism. The syndrome may also be associated with other physiological changes such as premature atherosclerosis, depletion of lean body mass, and other physiologic abnormities. As such, HADDS is a unique clinical entity in the history of medicine.
With respect to the invention described herein, it should be noted that a small percentage (probably fewer than ten percent) of HADDS patients in the United States have overt AIDS wasting (Muurahainen et al, unpublished observations, Serono Laboratories, Inc), although in probably more, if not all HADDS patients, occult wasting may be present. It should be noted that many patients with overt AIDS wasting are able to tolerate relatively high doses (6 mg/day) of recombinant growth hormone (rhGH; Serono's SEROTSIM) administered subcutaneously (s.c.), without developing adverse effects that require dose reduction or cessation of therapy (Schambelan et al, 1996).
In comparison to AIDS wasting patients, healthy (non-HIV infected, non-wasting) adults, when given 6 mg/day s.c. injections of rhGH will probably develop more symptomatology such as tissue turgor, joint stiffness, arthalgias, and/or paresthesias necessitating dose reduction or cessation of therapy (data on file, Serono Laboratories, Inc/, Norwell, Mass.). Dose-ranging trials are currently being designed to investigate the most effective and safe doses of rhGH for patients with HADDS, and to ascertain whether HADDS patients with occult and overt wasting are able to tolerate higher doses than HADDS patients without overt or occult wasting, if any.
Also with respect to the invention proposed herein, it should be noted that Bjorntorp and others (1996) have reported a disease entity termed metabolic syndrome X (or syndrome X), occurring in non-HIV-infected adults, that bears several similarities to HADDS. Patients with syndrome X typically present with mild to moderate visceral truncal adiposity, hyperlipidemia, insulin resistance, sometimes diabetes and hypertension, and occasionally associated with signs of premature atherosclerosis. However, this non-HIV related syndrome typically develops over many years. Moreover, compared to HADDS, syndrome X is not typically associated with (1) chronic HIV infection (2) excessive accumulation of adipose tissue in the visceral, dorsocervical, submandibular, supraclavicular, pectoral and/or mammary areas, (3) occasionally profound lipodystrophy or lipoatrophy of subcutaneous fat in the face, arms, legs, and/or buttocks, (4) lipomas, either multiple or single (if any at all), and (5) wasting, either overt or occult.
Other than for the invention proposed below, there is no currently known medical therapy that effectively treats the primary pathological abnormality of HADDS. Of course, there are a few approaches to the treatment of several abnormalities occasionally observed in patients with HADDS, such as hyperlipidemia, hyperinsulinemia/diabetes, wasting/cachexia, pancreatitis, gout, and hypogonadism. Sometimes these conditions can be managed in HADDS patients almost exactly as managed in non-HIV-infected patients.
However, the potential for reduction of the abnormal adipose tissue accumulation is uncertain. Since visceral adiposity, buffalo hump, and other fat accumulation in HIV-1-infected individuals with HADDS does not the result from Cushing's Syndrome (Lo et al, 1998), it would be unwise to treat it as such. Dietary modification and exercise are of limited success in reducing abnormally distributed regional fat accumulation such as buffalo hump and visceral adiposity (Kotler et al, personal communication). As described above, antiretroviral switch strategies have been disappointing at best. Saint-Marc (1999) has reported that the antihyperglycemic agent metformin may result in reduced total, subcutaneous, and visceral fat. However, because of its adverse effect profile, metformin may not be the best therapeutic agent to offer to most patients with HADDS.
Surgical interventions, such as liposuction and surgical excision, have been used with limited success to treat abnormally accumulated adipose tissue in the dorsocervical, submandibular, breast areas, or as lipomas. It is not feasible to liposuction abnormally accumulated visceral adipose tissue due to the risk of bowel perforation. Liposuction or plastic surgery produce only temporary relief, because the abnormal fat typical re-accumulates following surgical excision. Repeat surgical procedures augment risks of anesthesia and scarring. Moreover, the surgical techniques do not affect the metabolic abnormalities sometimes associated with HADDS.
SEROSTIM®, recombinant human growth hormone (rhGH) produced by Serono Laboratories, Inc., has recently been given accelerated FDA approval for treating wasting syndrome in patients with AIDS or AIDS-related cachexia.
Windisch et al (1998) reported that AIDS-associated wasting was characterized by weight loss, depletion of lean body mass and preservation of body fat, leading to muscle weakness and organ failure. Although the FDA has approved recombinant growth hormone for treating AIDS-associated wasting, the adverse event profile is similar to that of other recombinant growth hormone products. Trials of recombinant growth hormone on the control of wasting in patients with AIDS have been encouraging. Post-marketing experience with over 10,000 AIDS wasting patients receiving SEROSTIM® since 1996 reveals that a three-month course of therapy was effective in the majority of patients with AIDS wasting.
Krentz et al (1993) compared metabolic and anthropometric changes induced by recombinant human growth hormone dosed at 5.0 versus 2.5 mg every other day (qod) in 10 patients with HIV/AIDS. During treatment, insulin-like growth factor-1 (IGF-1) levels increased significantly in the pharmacological rhGH treatment group receiving 5.0 mg qod, whereas no significant change was observed in IGF-1 in the group receiving 2.5 mg qod of rhGH. In the group treated with 5.0 mg qod dose of hGH, weight loss preceding the study was reversed in each of the four patients who completed the study. This weight gain was associated with increases in lean body mass and total body water, and with concomitant decreases in fat mass and urinary nitrogen excretion.
In a large, randomized, placebo-controlled study, Schambelan et al (1996) used dual X-ray absorptiometery (DXA) scanning to evaluate changes in body composition produced by administration of recombinant human growth hormone dosed at 0.1 mg/kg/day (or 4 to 6 kg per day, depending on patient weight) compared to placebo over a 12 weeks course of therapy. By the end of treatment, significant increases in lean body mass and weight were observed in the rhGH group, compared to the placebo group, and these increases correlated with improvements in physical function (treadmill performance). The rhGH therapy was associated with minor increments in fasting plasma glucose, which were of negligible clinical significance.